Acute Pulmonary Thromboembolic Disease

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CHAPTER 97 Acute Pulmonary Thromboembolic Disease

Pulmonary embolism (PE) was clinically described in the early 1800s, and von Virchow first described the connection between venous thrombosis and PE.¹^,² In 1922, Wharton and Pierson reported the first radiographic description of PE,³ a commonly encountered entity whose diagnosis is clinically challenging because of its nonspecific symptoms.

Definition

Pulmonary thromboembolism is defined as the obstruction of the pulmonary artery or one of its branches leading to the lungs by a blood clot, usually from the leg, or foreign material causing sudden closure of the vessel. (Embolus is from the Greek embolos, meaning plug.) Emboli can also be composed of fat, air, or tumor tissue.

PE is a potentially fatal condition with substantial morbidity and mortality in untreated patients. The annual incidence of pulmonary embolism is estimated to be between more than 300,000 cases, resulting in approximately 50,000 to 100,000 deaths in the United States every year.⁴ Nearly 90% of PEs arise from lower extremity deep venous thrombosis (DVT). Diagnosis of pulmonary embolism remains a clinical challenge because of its nonspecific presentation. Mortality ranges from 3.5% to 15% and can be as high as 31% to 58% in the presence of shock.⁵^,⁶ Hence, prompt and accurate diagnosis is imperative because 65% of patients die within 1 hour of presentation and approximately 93% in the first 2.5 hours.⁷ Since its original description, imaging has played an important role in the diagnosis of PE. For many years, ventilation-perfusion (V/Q) scintigraphy has been the main imaging modality for the evaluation of patients with suspected PE. However, with the advent of and the widespread availability of faster computed tomography (CT) scanners, CT scanning has emerged as another important diagnostic test for the evaluation of not only PE but also DVT in select patients. Thus, familiarization with various aspects of imaging evaluation is of extreme importance for the interpreting physician.

Various imaging modalities are currently available to evaluate suspected PE in routine clinical practice. We will discuss current imaging options in the remainder of this chapter.

Etiology and Pathophysiology

Three primary influences predispose a patient to thrombus formation, which form the so-called Virchow triad: (1) endothelial injury; (2) stasis or turbulence of blood flow; and (3) blood hypercoagulability.^1,^2,⁸

More than 90% of all PEs arise from thrombi within the large deep veins of the legs, typically the popliteal vein and the larger veins central to it.^1,^2,⁴ The pathophysiologic consequences of thromboembolism in the lung largely depend on the cardiopulmonary status of the patient and on the size of the embolus, which in turn dictates the size of the occluded pulmonary artery.

PE has two important consequences: (1) an increase in pulmonary artery pressure produced by obstruction of flow, and possibly vasospasm caused by neurogenic mechanisms and/or release of mediators (such as thromboxane A2 and serotonin); and (2) ischemia of the downstream pulmonary parenchyma. Thus, occlusion of major vessels of more than 60% of the arterial bed suddenly increases pulmonary artery pressure, diminishes cardiac output, and causes right-sided heart failure (acute cor pulmonale) or even death. Usually, hypoxemia develops as a result of multiple mechanisms. If smaller vessels are occluded, the result is less catastrophic or the event may even be clinically silent.

MANIFESTATIONS

Clinical Presentation and Pretest Probability

Many patients with suspected PE present with nonspecific findings such as acute chest pain, and some are even asymptomatic. Some observers have suggested that because of the decline in tolerance for diagnostic uncertainty, diagnostic studies for the evaluation of PE may be overused in current practice. Pretest probability is an important concept, because the sensitivity, specificity, and predictive values of diagnostic imaging modalities are based on the pretest probability of PE, which is usually determined by clinical findings and laboratory test results.⁹^–¹¹ The Wells criteria (Table 97-1)¹² and Geneva score,¹³ which were devised and validated for clinical pretest probability, have been reported to have similar accuracy levels. Chagnon and colleagues¹⁴ have shown that these methods can be used to divide patients into low-, intermediate-, and high-probability groups for PE, although neither was accurate enough to diagnose PE in individual cases.

TABLE 97-1 Wells Clinical Decision Rule for Pulmonary Embolism

Variable	Points
Clinical signs and symptoms of deep vein thrombosis	3.0
Alternative diagnosis less likely than pulmonary embolism	3.0
Heart rate > 100/min	1.5
Immobilization (> 3 days) or surgery in the previous 4 weeks	1.5
Previous pulmonary embolism or deep vein thrombosis	1.5
Hemoptysis	1.0
Malignancy (receiving treatment; treated in the last 6 months or palliative)	1.0

Clinical probability of pulmonary embolism unlikely—4 points or less.

Clinical probability of pulmonary embolism likely—more than 4 points.

Adapted from Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83:416-420.

Serum D-dimer levels can be used to gauge the presence of PE. D-dimer is a fibrin degradation product that increases with clot lysis, suggesting the presence of thrombosis. It has been shown that this test with levels above a threshold value of 0.5 mg/L has an excellent sensitivity of 95%, but the specificity is lower (38% to 83%)¹⁵ because of elevated levels in some conditions, such as active inflammation, infection, pregnancy, malignancy, and liver failure. Of all the methods available for measurement of D-dimer levels (Table 97-2),¹⁰ the VIDAS D-dimer assay (bioMérieux, Marcy l’Etoile, France), a rapid, quantitative, enzyme-linked immunosorbent assay (ELISA) procedure, has been reported to have a 96.4% sensitivity,¹⁶ thus ruling out PE in the absence of a calculation of clinical pretest probability.¹⁶^,¹⁷ However, this is not routine clinical practice. Several studies^10,^11,¹⁸ have demonstrated that a negative result of rapid quantitative ELISA D-dimer can be combined with the clinical probability score to exclude PE in up to 40% of patients, thereby eliminating further workup.

TABLE 97-2 Sensitivity and Specificity (%) of D-Dimer Based on Laboratory Technique

Laboratory Technique	Mean (Range)
Laboratory Technique	Sensitivity	Specificity
ELISA	95 (85-100)	44 (34-54)
Rapid quantitative ELISA	95 (83-100)	39 (28-51)
Rapid semiquantitative ELISA	93 (79-100)	36 (23-50)
Rapid qualitative ELISA	93 (74-100)	68 (50-87)
Quantitative latex agglutination	89 (81-98)	45 (36-53)
Semi quantitative latex agglutination	92 (79-100)	45 (31-59)
Whole blood agglutination	78 (64-92)	74 (60-88)

ELISA, enzyme-linked immunosorbent assay.

Adapted from Ginsberg JS, Wells PS, Kearon C, et al. Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism. Ann Intern Med 1998; 129: 1006-1011.

Imaging Techniques and Findings

Chest Radiography

Initially, the chest radiography findings commonly are normal. However, in later stages, the radiograph may show findings that include a Westermark sign (dilation of pulmonary vessels and a sharp cutoff), atelectasis, a small pleural effusion, and an elevated diaphragm. Although chest radiographic findings may indicate an alternate diagnosis, this study alone is not sufficient to confirm the diagnosis of PE.

Chest radiographic findings of PE can be subtle, nonspecific, and infrequently present. Among the patients in a PIOPED study without any evidence of prior cardiopulmonary disease, 84% of patients with proven PE and 66% of those without PE had abnormal chest radiographs. In an actual clinical setting, certain findings may suggest a diagnosis of PE and direct further imaging.

The Westermark sign (Fig. 97-1)¹⁹ is a focal peripheral lucency beyond an occluded vessel accompanied by mild dilation of central pulmonary vessels, seen in 7% to 14% of cases of documented PE in the PIOPED study. It is a subtle finding caused by embolic obstruction or hypoxic vasoconstriction of pulmonary artery.

FIGURE 97-1 Westermark sign on chest radiograph showing oligemia of the right lung fields in comparison to the left lung. It denotes focal peripheral lucency beyond an occluded vessel accompanied by mild dilation of central pulmonary vessels.

Another finding is enlarged central pulmonary vasculature, which can be easily missed. It may be caused by vessel distention by thrombus or by an acute rise in pulmonary arterial pressure secondary to distal emboli. A sausage-like configuration of focal enlargement of the right descending interlobar pulmonary artery caused by the physical presence of a clot has also been noted in many patients with acute PE and referred to as the knuckle sign. Hampton hump ²⁰ is classically referred to as a conical peripheral opacity pointing toward the hilum. These are multiple, subpleural lower lobe infarcts seen as ill-defined opacities without air bronchography (Figs. 97-2 and 97-3).

FIGURE 97-2 Classic case of pulmonary embolism with Hampton hump sign showing subpleural infarct opacities on radiograph (A) and corresponding axial CT scans (B, C).

(Courtesy of Dr. Jeffrey P. Kanne, Cleveland Clinic, Cleveland, Ohio.)

FIGURE 97-3 A, B, Axial CT scans of 66-year-old patient with acute right upper lobe pulmonary embolism. B, The arrow points toward a developing infarct in the posterior segment of right upper lobe.

Focal parenchymal abnormalities are the most commonly encountered lesions on chest radiographs in PIOPED series patients. These particularly include subsegmental atelectasis (Fleischner lines),²¹ seen as linear opacities in lung bases; these are transient in nature and thought to be caused by mucus plugging, hypoventilation, or distant airway closure. Focal air space consolidation represents true pulmonary infarction, with ischemic necrosis or pulmonary hemorrhage without infarction occurring in 10% to 60% of patients. Small, unilateral, pleural effusions and diaphragmatic elevation are seen in a large number of PE patients.

In summary, the chest radiograph is often normal in patients with suspected PE. The sensitivity (33%) and specificity (59%) are low. The major role is in exclusion of conditions such as pulmonary edema, pneumonia, or pneumothorax, whose symptoms may overlap with those of PE. In addition, chest radiographs are used for correlation of the interpretation of V/Q scintigraphy results.

Lower and Upper Extremity Ultrasonography

As noted, 90% of PEs originate from thrombosis within the deep venous system of the lower extremities and are mostly clinically silent; other sources are the pelvic, renal, and upper extremity veins.²² Significant morbidity and mortality are associated with undiagnosed DVT; thus, methods such as contrast venography (CV), magnetic resonance venography (MRV), and lower extremity ultrasonography are commonly used for its detection. Real-time gray scale, continuous wave and pulsed Doppler, and color Doppler imaging, along with ancillary techniques such as the Valsalva maneuver and manual blood flow augmentation, are used to image the lower extremity veins.

Acute thrombus is often anechoic with variable echogenicity, making compression ultrasonography an important tool for assessment. The diagnosis is established by lack of venous compression caused by intraluminal thrombus. Lack of appropriate response to a Valsalva maneuver also indicates thrombosis of the central veins outside the field of view. The reliability of a negative compression ultrasonography examination is high.

Spectral Doppler analysis is particularly useful for vessels that cannot be visualized directly, such as the inferior vena cava ( IVC), superior vena cava (SVC), and brachiocephalic veins. Normal patent vessels show respiratory phasicity, whereas a monophasic waveform suggests venous obstruction.

Color Doppler imaging is useful to identify deeper veins such as the iliac veins and superficial femoral veins, for which direct venous compression is not possible, or for obese or swollen extremity patients. Thrombosis is identified as the absence of color flow within a vessel lumen at baseline and with augmentation; the sensitivity and specificity are 95% and 98%, respectively, for femoropopliteal DVT.²²

Upper extremity thrombosis is screened using spectral and color Doppler techniques for veins inaccessible to direct compression. The incidence of PE with upper extremity DVT may be as high as 12% to 15%, making these diagnostic tests highly significant.

In summary, color flow Doppler imaging and compression ultrasonography have a high sensitivity (89% to 100%) and specificity (89% to 100%) for the detection of proximal DVT in symptomatic patients. However, compression ultrasonography has a low sensitivity (38%) and a low positive predictive value (26%) in patients without symptoms of DVT. Patients with positive findings for DVT can be anticoagulated irrespective of their V/Q scan results; other patients must have more invasive investigations performed to rule out PE definitively.

Ventilation-Perfusion Scintigraphy

V/Q scanning of the lungs is an important diagnostic modality for establishing the diagnosis of PE. The PIOPED classification scheme allows for a more meaningful interpretation of the V/Q scan to treat patients with anticoagulation. The scans should be interpreted primarily as a diagnostic or nondiagnostic pattern, indicating whether the patient has or does not have a high likelihood of having PE.

A normal perfusion scan excludes a diagnosis of PE, with its negative predictive value close to 100%.²³^–²⁵ It is a safe, relatively inexpensive, and widely available test that allows the acquisition of single-breath, equilibrium, and washout images. A high-probability V/Q scan (Figs. 97-4 and 97-5), in combination with high-probability clinical findings, corresponded to PE in 96% of patients, whereas a low-probability clinical assessment showed PE in only 4% of patients in a major study.⁹

FIGURE 97-4 Anterior projection of a Tc 99m diethylenetriamine pentaacetic acid (DTPA) aerosol image demonstrates relatively homogeneous ventilation.

(Courtesy of Dr. Donald Neumann, Cleveland Clinic, Cleveland, Ohio.)

FIGURE 97-5 Left posterior oblique (A) and right lateral planar (B) views of Tc 99m macroaggregated albumin pulmonary perfusion scans show multiple large perfusion defects compatible with a high-probability scan in a patient with pulmonary embolism.

(Courtesy of Dr. Donald Neumann, Cleveland Clinic, Cleveland, Ohio.)

In PIOPED-1, a V/Q scan in patients with a normal chest radiograph was diagnostic in 52% of patients with suspected PE,²⁶ and one study has shown it to be diagnostic in 91% of patients.²⁷ This PIOPED group retrospectively analyzed perfusion scans alone and found the results to be equivalent to those of the V/Q technique.²⁸ In the PISA-PED trial,²⁹ only perfusion scans were obtained. These were classified according to the shape of defects, yielding sensitivity and specificity of 86% and 93%, respectively, for abnormal perfusion scans compatible with PE, with the result being dichotomous. These studies indicate that the ventilation scan can be eliminated, thus reducing cost and radiation dose. It can also be used as a preferred alternative for patients unable to undergo CT angiography.

It can be used particularly for reproductive female patients whose chest radiograph is likely to be normal and in whom the breast irradiation dose from CT angiography can be minimized using the perfusion scan only.⁹^,³⁰ Another significant use is follow-up of proven PE patients undergoing anticoagulation.

Ventilation-Perfusion Single Photon Emission Computed Tomography

V/Q single photon emission computed tomography (SPECT) is a newer modality that may improve both sensitivity and specificity of the V/Q scan (Fig. 97-6). Reinartz and associates³¹ analyzed 83 patients who underwent four-slice spiral CT, V/Q planar, and V/Q SPECT studies, giving sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of 97%, 91%, 98%, and 90%, respectively, for SPECT techniques. This study used aerosolized technetium 99m (Tc 99m) for the ventilation portion of the V/Q scan instead of the radioisotope xenon 133. Tc 99m is five times smaller in diameter and has a 20% efficiency of pulmonary deposition in comparison to 2% for xenon 133, thus helping improve the results.³²^,³³ Unlike PIOPED, this study considered all the mismatched results as PE, regardless of the size. This technique has the potential to improve the interpretation of V/Q scanning by incorporating computerized interpretations.

FIGURE 97-6 Fused sagittal (A) and transverse (B) Tc 99m macroaggregated albumin SPECT/CT tomograms of a 67-year-old male patient show lack of perfusion associated with the inferior lingular segment. Subsequently, this patient was diagnosed to have acute pulmonary embolism.

(Courtesy of Dr. Donald Neumann, Cleveland Clinic, Cleveland, Ohio.)

Thus, a normal V/Q SPECT scan is a sensitive and safe test for PE evaluation and may be especially useful for renal failure patients. Initial studies using SPECT technique with Tc 99m are promising and suggest improved accuracy of V/Q scanning, but further prospective studies are needed to incorporate its use in daily practice.

Pulmonary Angiography

This method had served as a standard of reference for PE detection for decades before the advent and widespread use of CT. It was usually performed in cases of discrepancy between the clinical suspicion and results of the V/Q scan, or if there were coexisting conditions (e.g., pneumonia, lung cancer) that could result in a false-positive result. Angiography was also often performed prior to interventions such as mechanical clot fragmentation. The relative contraindications to this procedure are listed in Box 97-1.²²

Box 97-1

Adapted from Gotway MB, Reddy GP, Dawn SK: Pulmonary thromboembolic disease. In Webb WR, Higgins CB (eds). Thoracic Imaging. Philadelphia, Lippincott Williams & Wilkins, 2005, pp 609-629.

Relative Contraindications to Pulmonary Angiography

Documented allergy to contrast materials

Elevated right ventricular end-diastolic pressure (greater than 20 mm Hg) and/or increased pulmonary artery pressure over 70 mm Hg

Left bundle branch block

Renal insufficiency or failure

Bleeding diatheses

Pulmonary angiography has high specificity rates, approaching almost 100% for a filling defect or abrupt pulmonary arterial obstruction. Other findings for acute PE include delayed venous return, decreased pulmonary flow, and tortuous vessels. In the past, a negative pulmonary angiogram was thought to exclude the diagnosis of clinically significant PE, but there is currently some controversy regarding this conclusion.

Major complications (1% to 3%) associated with the procedure include respiratory distress requiring resuscitation, cardiac perforation, contrast reactions, major dysrhythmias, renal failure, and hematomas. Minor complications (5%) are contrast-induced renal dysfunction, respiratory distress, angina, minor contrast reaction, and transient dysrhythmias.

Computed Tomography of the Chest

CT Pulmonary Angiography

The role of a multidetector CT (MDCT) scan for the diagnosis of PE has evolved over the last decade. MDCT can visualize main, lobar, and segmental pulmonary emboli with a reported sensitivity of greater than 90%. Multidetector CT scanning can detect emboli as small as 2 mm that affect up to the seventh-order arterial division. Small subsegmental emboli may not be detected, although the advent of faster scanners has allowed even these small and likely clinically insignificant emboli to be readily seen with increasing frequency. CT has another benefit—an alternate diagnosis may be suggested in up to 57% of patients.

Single-detector helical CT pulmonary angiography (SCTA) is an older technique that is still in clinical use. It has a reported high accuracy, with sensitivity reported to range from 60% to 100% and specificity from 81% to 100%.³⁴^,³⁵ This technique involves the use of a single detector and x-ray source that rotate around the patient, taking multiple cross-sectional images and allowing the entire study to be completed in 25 to 30 seconds. When it was first developed it represented an important advance, because it allows over 90% of patients to hold their breaths throughout the study, thus reducing motion artifact from breathing.³⁶ Also, 3-mm slices can be obtained with the spiral technique which aid in higher quality imaging of the vasculature. By 2001, at many institutions, SCTA had surpassed the V/Q scan as the initial test for evaluation of PE.

There have been a few published reports challenging the accuracy of SCTA, reporting a high specificity and low sensitivity in the evaluation of PE. Most of these studies concluded that SCTA was inadequate as a single first-line test for PE evaluation, especially for acute thrombi in subsegmental pulmonary arteries and right middle lobe and lingular arteries.³⁴^,³⁵ Several follow-up studies were performed to determine whether the sensitivity of SCTA could be improved. Perrier and coworkers³⁷ found in 299 patients that SCTA combined with lower extremity ultrasonography yielded only a 70% sensitivity, despite the fact that ultrasonography yielded better false-negative rates. In another similar study, approximately 16% of the negative SCTA had positive lower extremity ultrasonography needing treatment.³⁸ Thus, it was suggested that a negative SCTA along with lower extremity ultrasonography was important for ruling out a diagnosis of PE.

Technical Considerations

A specific imaging protocol is designed to optimize the diagnostic information, giving particular attention to various scan parameters to obtain high-quality images. Ideally, for a helical CT scan, it must include the entire pulmonary arterial system, without the other areas of thorax, to reduce radiation exposure and keep the timing of the study optimal. A caudocranial scanning direction is beneficial because most PEs are detected in the lung bases, where the blood flow is maximal. Therefore, even if the patient loses his or her breath-hold, the degradation of scan quality from motion would most likely occur in the upper lung region, where PE occurrence is less likely. An inspiratory breath-hold is desirable because it can increase the pulmonary vascular resistance, leading to better contrast enhancement. Various concentrations of contrast agent and protocols for injection rate have been used, each with its own advantages and disadvantages. High-contrast agent concentration (300 to 360 mg/mL) with a high rate of infusion (3 mL/second or higher) is the most popular, convenient, and effective because it maximizes pulmonary artery opacification and allows the use of preloaded syringes. Typically, 2- to 3-mm collimation imaging is done with or without narrow overlapping reconstruction. This technique provides excellent image quality, but also leads to a larger data storage requirement. Additionally, it is preferable to use larger pitch values with narrower collimation. Pitch values of 1.7 to 2 are commonly used. Also, proper timing of the contrast bolus is extremely important to obtain a high-quality image. Generally, a presumptive scan delay of 20 seconds for upper extremity injections works well to obtain adequate enhancement. Rapid viewing of contiguous scans in sequence is useful in clinical practice. Multiplanar reformatted images can be useful to identify small artery abnormalities, which usually follow an oblique course, and three-dimensional reconstructions with volume rendering aid in displaying complex anatomy.²²

Classic Findings

A diagnosis of acute PE is established when a partial intraluminal filling defect is visualized with a sharp interface surrounded by varying degree of contrast (Fig. 97-7). Eccentric or peripheral intraluminal filling defects form acute angles with the vessel wall. Acute PE thrombus attenuation measures 33 ± 14 HU, whereas that of chronic PE thrombus measures 90 ± 30 HU. There are two very reliable signs for acute PE diagnosis—a thrombus usually appears to be central in the pulmonary artery when seen in cross section (the doughnut sign). Occasionally, it may be outlined by contrast agent when imaged along its axis (railroad track sign).²² Other findings include mosaic perfusion, right ventricular strain (Fig. 97-8), peripheral consolidation (representing pulmonary hemorrhage or infarction), and pleural effusions. Saddle embolus bridges can form across the right and left main pulmonary arteries and are a cause of sudden death (Fig. 97-9). Mosaic perfusions are inhomogeneous lung opacities caused by alteration in pulmonary blood flow. The Miller method³⁹ is commonly used to measure the clot burden and indicates the severity of PE, but is a poor predictor of mortality. In this method, 1 point is given for a clot in each proximal artery, which is equivalent to each segment arising distally, thus resulting in a maximum score of 9 for right lung, 7 for left lung, and 16 total.

FIGURE 97-7 Axial view CT scan of a 49-year-old patient depicting a massive central embolism.

FIGURE 97-8 CT scan showing marked enlargement of right ventricle, with associated compression of the left ventricle denoting right ventricular strain.

FIGURE 97-9 CT scan, axial view, of a 56-year-old patient with a saddle embolus bridging across the right and left main pulmonary arteries.

Benefits and Accuracy

SCTA has high specificity rates, making a positive result highly likely to be PE. Moreover, CT directly depicts a thrombus, thereby eliminating false-positive results caused by factors such as radiation effects and extraluminal compression. CT allows imaging of the lung parenchyma, chest wall, and mediastinum, reducing the need for additional studies to make a diagnosis if PE is absent. This is important, because neither V/Q scan nor pulmonary angiography can detect other conditions reliably.

The accuracy of diagnosis depends on the size of the artery affected and the size of the emboli (clot burden). CT has a diagnostic accuracy of almost 100% for acute emboli in large pulmonary arteries. It has also been shown to have higher sensitivity and specificity in comparison to V/Q scintigraphy. A confident diagnosis can be made in 90% of patients because, even in those in whom a scan is interpreted as negative, an alternative diagnosis can be established. Furthermore, transthoracic and transesophageal echocardiography have proved to be of limited accuracy in the diagnosis of PE in an acute setting. Controversies regarding the accuracy for diagnosis have been reflected in various studies in different populations (see further discussion in the next section).

Limitations

Pooled data from numerous studies have suggested a sensitivity of 90% and specificity over 90% in cases of suspected acute PE involving main, lobar, and segmental arteries, although a wider range has been observed in many studies. Contributing to the lower sensitivity is its resolution. The sensitivity and specificity rates are particularly diminished (61% to 79% at its best) for small subsegmental emboli, which are usually uncommon in an acute setting.³⁴^,⁴⁰ Between 6% and 30% of patients with PE have isolated subsegmental emboli.⁴¹ Thus, studies that demonstrated the lowest sensitivity rates mainly consisted of patients with small thrombi.

CT scanning leads to significant radiation exposure; for all indications, it accounts for approximately 40% to 75% of medical radiation exposure.⁴²^,⁴³ This increases the risk of malignancy in patients involved in serial studies. The radiation dose to the breast is of special concern. This radiation exposure is also an issue of concern for pregnant women.

Another limitation to be taken into account is reaction to the contrast medium used. Nearly 15% of patients experience mild reactions such as nausea, vomiting, and flushing.⁴⁴ Severe reactions are less frequent; these include laryngeal edema, bronchospasm, convulsions, and cardiovascular collapse (0.04% to 0.22%). The incidence of these reactions is reduced substantially by using low-osmolality contrast media. Contrast-induced nephropathy (CIN) is another important life-threatening complication. Furthermore, patients with preexisting primary conditions such as pregnancy and renal failure are contraindicated from the use of this test.

Anatomic pitfalls include normal hilar lymph nodes, which simulate acute PE, pulmonary vein artifacts being confused with arterial filling defects, partial volume averaging of anterior segmental artery creating an effect of intraluminal filling defect and, rarely, a calcified bronchus with mucoid impaction suggests a defect surrounded by contrast.

Multidetector Computed Tomography

MDCT became available for clinical use in the late 1990s and is now widely accepted as the standard of care. In this technique, multiple detectors are rotated as the patient slides through the CT scanner gantry. In its earliest form, MDCT used four scanners. However, that number gradually increased to 64-detector technology, which is widely used currently, and scanners with 256 detectors or more are or will be available in the near future. The increase in the number of detectors has led to a reduction in study time by 10 seconds and slice thickness as low as 0.5 mm, greatly contributing to higher resolution and imaging, up to sixth-order pulmonary arteries.⁴⁰ This has consequently led to improved detection of subsegmental PEs, higher sensitivity rate, and reduction in false-negative results. The coronal, sagittal, and axial reconstructions using thin axial collimation have different sensitivities and may aid in the reduction of artifacts and false-positive rates by three-dimensional visualization. Thin collimation also allows retrospective reconstruction of CT images using electrocardiographic reconstruction based on the R-R interval, which eliminates cardiac artifact and helps obtain better visualization of the coronary arteries and thoracic aorta.

Several studies have validated the use of MDCT for the evaluation of PE. The first evaluated patients with high clinical probability or an abnormal D-dimer test by the Geneva score.⁴⁵ In the second study, inpatients and outpatients were evaluated with abnormal D-dimer or PE-like clinical probability by a modified Wells score.¹¹

In the PIOPED II multicenter trial, 1090 patients were enrolled; 824 underwent CT pulmonary angiography (CTPA), CT venography (CTV), and a confirmatory test. Of these, 192 patients (24%) had PE and 51 patients (6%) had an inadequate CTPA result.⁴⁶ The primary aim of PIOPED II was to determine the accuracy of MDCT for the diagnosis and exclusion of PE in suspected patients. The observed sensitivity was 83% specificity was 96%, and 87 patients (11%) had an inadequate CTV result. The combined sensitivity and specificity of CTA-CTV were 90% and 95%, respectively. This led to the conclusion that MDCT CTA-CTV is more accurate than CTPA alone for the diagnosis of PE. It also established that in the case of the clinical picture being dissonant with CTPA, further imaging should be undertaken. Because V/Q scanning was the reference test in this study, any discordance with CTPA led to the incorporation of another test, such as a positive lower extremity ultrasonography, low-probability V/Q, and low clinical probability using Wells criteria or a positive digital subtraction angiography (DSA) result. Additionally, the PIOPED investigators created a composite standard, which, if satisfied, could diagnose or exclude PE, in case MDCT was positive, with a negative angiography result. This is a powerful set of tests that can be reliably used for the exclusion of PE without pulmonary angiography or CT scanning (Table 97-3). The main limitation was the use of clinical probability as the decision point.

TABLE 97-3 Diagnostic Reference Standard for Prospective Investigation of Pulmonary Embolism Disorders (PIOPED) II

PE Diagnosed	PE Excluded
High-probability V/Q scan in patient without prior history of PE	Normal findings on digital subtraction pulmonary angiography
Abnormal findings on pulmonary digital subtraction angiography	Normal findings on V/Q scan
Abnormal findings on venous ultrasonography in patient with no prior history of DVT at that site and nondiagnostic V/Q scan (not normal and not high probability)	Low or very low probability V/Q scan in subject with clinical Wells score <2 and negative lower extremity ultrasonography

DVT, deep venous thrombosis; PE, pulmonary embolism; V/Q, ventilation-perfusion.

Adapted from Stein PD, Fowler SE, Goodman LR, et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 2006; 354: 2317-2327.

Limitations

Important limitations include unsatisfactory images caused by respiratory and cardiac motion. MDCT detects PEs at a subsegmental level, especially involving fifth- and sixth-order branch vessels, which have lower significance but immediate importance. They may not be of acute danger to the patient but predict a future, more severe embolism. Thus, the incidence of PE should be higher in MDCT studies than in those performed with other methods. It was 33% for the original PIOPED study,⁹ whereas only 20.4% to 26% for the newer PIOPED II, Perrier, and Christopher studies.¹¹^,⁴⁵

MDCT also exposes patients to significantly greater radiation exposure and a further increased risk of CIN; 25% of patients will have a contraindication such as pregnancy or renal insufficiency. Also, patients allergic to contrast media are contraindicated. Finally, although MDCT scanners are an excellent modality for detection of PE, the number of scans should be limited because of side effects.

Computed Tomography Venography

CTV provides the additional ability to image DVT in the pelvic veins as well as the lower extremity venous system immediately following CT angiography of the pulmonary arterial system, without administration of additional contrast. The thrombi are visible as filling defects within the veins. Such a technique not only expedites patient evaluation, but also provides a diagnostic benefit over ultrasound assessment. A large cohort study conducted by Cham and colleagues ⁴⁷ has shown a 20% increase in the detection of thromboembolism when CTV was performed with contiguous, helically acquired 10-mm sections in comparison to CTA alone. As noted, a PIOPED II trial clearly reported that the sensitivity of CTA for the diagnosis of PE increased from 83% to 90% with the addition of CTV.⁴⁶ Thus, the addition of CTV is beneficial for better diagnosis and further treatment planning for patients with suspected PE undergoing CTA studies.

Magnetic Resonance Imaging

Recent advances in the field of MRI technology has made this challenging field useful for the imaging of pulmonary vascular structures. The reduction in breath-hold time to 20 seconds (as a result of the acquisition of all the images in a shorter time) had led to its increased popularity.⁴⁸ Although many challenges exist, such as a relative lack of signals in lieu of paucity of protons in chest, air, and soft tissue interface artifacts, and respiratory and cardiac motion problems, it is still attractive for two primary reasons. First, and most important, MRI overcomes the use of ionizing radiation to generate images, making it completely harmless to the patient. Hence, it is being considered safe in pregnancy as well. Secondly, intravenous contrast agents are considered less nephrotoxic.